Oral suspension of apremilast

Abstract

Provided herein are suspensions for oral administration comprising a) apremilast, b) a suspending agent, c) a sweetener, d) one or more of a vehicle, a co-solvent, a buffering agent, a preservative, or a combination thereof. Also provided herein is a suspension for oral administration comprising a) apremilast, b) microcrystalline cellulose/carboxymethylcellulose sodium, c) xanthan gum, d) sucrose, e) sorbitol, f) glycerin, g) propylene glycol, h) citric acid monohydrate, i) methylparaben, j) propylparaben, and h) water.

What is claimed: 
     
         1 . A suspension for oral administration comprising:
 a. apremilast;   b. a suspending agent;   c. a sweetener;   d. one or more of a vehicle, a co-solvent, a buffering agent, a preservative, or a combination thereof; and   e. water.   
     
     
         2 . The suspension of  claim 1 , wherein the apremilast is present in the suspension in a total concentration of 3 to 10 mg/mL. 
     
     
         3 . The suspension of  claim 2 , wherein the apremilast is present in the suspension in a total concentration of 5 mg/mL. 
     
     
         4 . The suspension of any one of  claims 1-3 , wherein the suspending agent comprises microcrystalline cellulose, carboxymethylcellulose sodium, methyl cellulose, ethyl cellulose, xanthan gum, xanthine gum, carrageenan; guar gum, locust bean gum, a carbomer, magnesium aluminum silicate (Veegum), or a combination thereof. 
     
     
         5 . The suspension of  claim 4 , wherein the suspending agent comprises a blend of microcrystalline cellulose and carboxymethyl cellulose sodium (microcrystalline cellulose/carboxymethyl cellulose sodium blend) and xanthan gum. 
     
     
         6 . The suspension of  claim 5 , wherein the microcrystalline cellulose/carboxymethyl cellulose sodium blend and xanthan gum are present in a concentration ratio of 3.4:1 to 4:1 or less. 
     
     
         7 . The suspension of  claim 6 , wherein the ratio is 3.7:1. 
     
     
         8 . The suspension of any one of  claims 1-7 , wherein the suspending agent is present in the suspension in a total concentration of 8.5 mg/mL. 
     
     
         9 . The suspension of any one of  claims 1-8 , wherein the sweetener comprises sucrose, sorbitol, aspartame, fructose, lactose, or a combination thereof. 
     
     
         10 . The suspension of  claim 9 , wherein the sweetener comprises sucrose and sorbitol. 
     
     
         11 . The suspension of  claim 9 or 10 , wherein the sweetener is present in the suspension in a total concentration of 500 mg/mL or less. 
     
     
         12 . The suspension of  claim 11 , wherein the sweetener is present in the suspension in a total concentration of 380 mg/mL. 
     
     
         13 . The suspension of any one of  claims 1-9 , wherein the sweetener comprises sucrose in a concentration of 150 to 225 mg/mL and sorbitol in a concentration of 150 to 225 mg/mL. 
     
     
         14 . The suspension of  claim 13 , wherein the sweetener comprises sucrose and sorbitol in a concentration ratio of 1 to 1. 
     
     
         15 . The suspension of any one of  claims 1-14 , wherein the suspension comprises a vehicle. 
     
     
         16 . The suspension of  claim 15 , wherein the vehicle comprises glycerin. 
     
     
         17 . The suspension of  claim 15 or 16 , wherein the vehicle is present in the suspension in a total concentration of 100 mg/mL to 200 mg/mL. 
     
     
         18 . The suspension of  claim 17 , wherein the vehicle is present in a total concentration of 133 g/mL. 
     
     
         19 . The suspension of any one of  claims 1-18 , wherein the suspension comprises a co-solvent. 
     
     
         20 . The suspension of  claim 19 , wherein co-solvent comprises propylene glycol. 
     
     
         21 . The suspension of  claim 19 or 20 , wherein the co-solvent is present in the suspension in a total concentration of 10 mg/mL to 20 mg/mL. 
     
     
         22 . The suspension of  claim 21 , wherein the co-solvent is present in a total concentration of 14 mg/mL. 
     
     
         23 . The suspension of any one of  claims 1-22 , wherein the suspension comprises a buffering agent. 
     
     
         24 . The suspension of  claim 23 , wherein the buffering agent comprises citric acid or a hydrate thereof, a citric acid salt, tartaric acid, tartaric acid salt, ascorbic acid, ascorbic acid salt, phosphoric acid, phosphoric acid salt, acetic acid, acetic acid salt, or a combination thereof. 
     
     
         25 . The suspension of  claim 24 , wherein the buffering agent comprises citric acid monohydrate. 
     
     
         26 . The suspension of any one of  claims 23-25 , wherein the buffering agent is present in the suspension in a total concentration of 1 mg/mL to 5 mg/mL. 
     
     
         27 . The suspension of  claim 26 , wherein the buffering agent is present in a total concentration of 1.8 mg/mL. 
     
     
         28 . The suspension of any one of  claims 1-27 , wherein the suspension comprises a preservative. 
     
     
         29 . The suspension of  claim 28 , wherein the preservative comprises methylparaben, propylparaben, or a combination thereof. 
     
     
         30 . The suspension of  claim 29 , wherein the preservative comprises methylparaben and propylparaben. 
     
     
         31 . The suspension of  claim 30 , wherein the methylparaben and propylparaben are present in a concentration ratio of 9 to 1. 
     
     
         32 . The suspension of any one of  claims 28-31 , wherein the preservative is present in the suspension in a total concentration of 1 mg/mL to 2.5 mg/mL. 
     
     
         33 . The suspension of  claim 32 , wherein the preservative is present in a total concentration of 1.7 mg/mL. 
     
     
         34 . The suspension of any one of  claims 30-32 , wherein methylparaben is present in a concentration of 0.9 mg/mL or more and propylparaben is present in a concentration of 0.1 mg/mL or more. 
     
     
         35 . A suspension for oral administration comprising a) apremilast, b) a blend of microcrystalline cellulose and carboxymethylcellulose sodium, c) xanthan gum, d) sucrose, e) sorbitol, f) glycerin, g) propylene glycol, h) citric acid monohydrate, i) methylparaben, j) propylparaben, and h) water. 
     
     
         36 . The suspension of  claim 35  comprising a) 5 mg/mL apremilast, b) 6.7 mg/mL of the blend of microcrystalline cellulose and carboxymethylcellulose sodium, c) 1.8 mg/mL xanthan gum, d) 190 mg/mL sucrose, e) 190 mg/mL sorbitol, f) 133 mg/mL glycerin, g) 14 mg/mL propylene glycol, h) 1.8 mg/mL citric acid monohydrate, i) 1.5 mg/mL methylparaben, j) 0.17 mg/mL propylparaben, and h) water. 
     
     
         37 . The suspension of  claim 35  comprising a) 5 mg/mL apremilast, b) 6.7 mg/mL of the blend of microcrystalline cellulose and carboxymethylcellulose sodium, c) 1.8 mg/mL xanthan gum, d) 190 mg/mL sucrose, e) 190 mg/mL sorbitol, f) 133 mg/mL glycerin, g) 14 mg/mL propylene glycol, h) 1.8 mg/mL citric acid monohydrate, i) 0.9 mg/mL methylparaben, j) 0.10 mg/mL propylparaben, and h) water 
     
     
         38 . The suspension of  claim 35  comprising a) 5 mg/mL apremilast, b) 6.7 mg/mL of the blend of microcrystalline cellulose and carboxymethylcellulose sodium, c) 1.8 mg/mL xanthan gum, d) 190 mg/mL sucrose, e) 190 mg/mL sorbitol, f) 133 mg/mL glycerin, g) 14 mg/mL propylene glycol, h) 1.8 mg/mL citric acid monohydrate, i) 1.1 mg/mL methylparaben, j) 0.12 mg/mL propylparaben, and h) water 
     
     
         39 . The suspension of  claim 35  comprising a) 5 mg/mL apremilast, b) 6.7 mg/mL of the blend of microcrystalline cellulose and carboxymethylcellulose sodium, c) 1.8 mg/mL xanthan gum, d) 190 mg/mL sucrose, e) 190 mg/mL sorbitol, f) 133 mg/mL glycerin, g) 14 mg/mL propylene glycol, h) 1.8 mg/mL citric acid monohydrate, i) 1.2 mg/mL methylparaben, j) 0.14 mg/mL propylparaben, and h) water 
     
     
         40 . The suspension of any one of  claims 1-39 , having an AUC of 90% to 110% of the AUC of an immediate-release oral apremilast tablet of comparable apremilast strength upon administration to a patient under fasting conditions. 
     
     
         41 . A method of treating a patient suffering from a disease or disorder ameliorated by inhibiting PDE4 comprising administering to the patient the suspension of any one of  claims 1-40 . 
     
     
         42 . The method of  claim 41 , wherein the disease or disorder is psoriasis, psoriatic arthritis, or Behcet's disease. 
     
     
         43 . The method of  claim 41 or 42 , wherein the patient is a pediatric patient. 
     
     
         44 . A packaged suspension comprising the suspension of any one of  claims 1-40 , a bottle, and a stopper.